Chance, Genetics, and the Heterogeneity of Autoimmunity and Disease Pathogenesis in Systemic Lupus Erythematosus

Phylogenetic and ontogenetic evolution combine to maximize the potential for the immune system to detect and eliminate pathogens at risk for initiating potentially damaging immune reactions including self-reactivity and autoimmune disease. Innate immune receptors have limited diversity and detect molecules whose expression is exclusive or at least more prevalent among pathogens, for example lipopolysaccharide and DNA with non-methylated CpG, respectively. Adaptive immune receptors, on the other hand, have enormous diversity and include those with reactivity to self. Intrinsic and extrinsic cellular and molecular mechanisms function to prevent maturation of adaptive immune cells with self-reactive receptors and limit and control self-reactive or otherwise harmful innate and adaptive immune responses when they occur. Failure of the regulatory control mechanisms can lead to excessive acute inflammation, allergy, chronic inflammation, or autoimmune disease.

Systemic lupus erythematosus (SLE) is a genotypically and phenotypically heterogeneous, systemic autoimmune disease that affects multiple organs and connective tissues. Glomerulonephritis is the most severe disease manifestation in SLE and has the highest standardized mortality ratio among patients. Prominent among the autoantibody specificities in SLE and the specificity most correlated with glomerulonephritis is autoantibody to DNA. Our research in experimental models of SLE have improved our understanding of how autoantibodies to DNA initiate glomerulonephritis and why there is such heterogeneity in kidney disease among SLE patients with otherwise identical serum autoantibody profiles.